The construction of basic heterocyclic structures is one of the most important synthetic steps in organic chemistry. The heterocyclic compounds are of great significance, inter alia, as intermediates in the synthesis of active pharmaceutical ingredients and active crop protection ingredients, or else directly as such active ingredients. In addition, the rapid synthesis, which is particularly important in the preparation of screening substances, analogs of which are sometimes quite diverse in structural terms, places high demands on synthesis planning. Central building blocks which allow direct access to a multitude of diverse heterocycles under similar, or ideally identical, reaction conditions are therefore particularly valuable and of great significance, in particular for robot-assisted syntheses.
The synthesis of heterocycles starting from thioureas has been known for some time. However, the methods have limitations in substrate selection or disadvantages in reaction control, workup, by-product removal or in the cost of reagents. For instance, 1-(2-hydroxyethyl)-3-arylthioureas can be cyclyzed by heavy metal derivatives, such as mercury (II) oxide or lead oxide, to give oxazolidin-2-ylidenarylamines (Jen, et al., J. Med. Chem. 1975 (18), 90). Acid catalysis of the same reactants affords the corresponding arylthiazolidin-2-ylidenamines (Jen, et al., J. Med. Chem. 1975 (18), 90). However, the use of heavy metals is disadvantageous, since they are unwanted in the product, even only in trace amounts. The acid-catalyzed conversion to the thiazolidine again proceeds satisfactorily only at elevated temperatures and in the presence of high acid concentrations. These drastic conditions are not tolerated by some functionalities, such as esters, nitrites and ketals.
Syntheses starting from 1-(2-aminoethyl)-3-arylthioureas to imidazolidin-2-ylidenaryl derivatives succeed in the presence of methyl iodide (Synthesis 1974, 41-42) or carbodiimide derivatives (Synthesis 1977, 864). A disadvantage in the case of methyl iodide is the competing reaction which occurs on other nucleophilic centers in the molecule and the consequent potential danger in the event of unintentional release. In the case of carbodiimide derivatives, the removal of the ureas formed is frequently problematic and time-consuming. More recent carbodiimide derivatives such as EDC (N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride) or solid phase-bound DCC (dicyclohexylcarbodiimide), used in a relatively large amount, are again very expensive.